Nemategravir triethylene diamine eutectic crystal as well as preparation method and application thereof

Abstract

The invention discloses a nemategravir triethylene diamine eutectic crystal as well as a preparation method and application thereof. Specifically, the invention provides a eutectic crystal of a compound as shown in a formula I, and a preparation method and application of the eutectic crystal. The co-crystal has one or more advantages as follows: (1) the co-crystal has better solubility, is easier to preserve and is suitable for new drug development and industrial production; (2) the process route is simple, and the cost is low; and (3) the tablet has a relatively uniform particle size and is suitable for preparation tabletting production. # imgabs0 #

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technologies, and particularly to nirmatrelvir triethylenediamine cocrystal, its preparation method and its application. Background Art

[0002] Nirmatrelvir, chemical name: (1R,2S,5S)-N-[(1S)-1-cyano-2-(2-oxopyrrolidin-3-yl)ethyl]-3-[(S)-3,3-dimethyl-2-(trifluoroacetamido)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, and its structural formula is as follows:

[0003]

[0004] Nirmatrelvir is a 3CL protease inhibitor and plays an important role in the life cycle of many COVIDs. Its potential advantage is that it can act on all current COVID-19 variants. Moreover, its mechanism of action is significantly different from that of the approved anti-COVID-19 drugs remdesivir and molnupiravir, which inhibit COVID-19 by cleaving long polypeptide chains. Considering the great use of Nirmatrelvir in the treatment of COVID-19, it is necessary to study its crystal forms.

[0005] Patent CN114644681A discloses a nirmatrelvir isopropanol solvate crystal form and its preparation method, specifically discloses a nirmatrelvir isopropanol solvate crystal form and its preparation method. The original research company Pfizer's patent discloses two crystal forms, namely the nirmatrelvir API crystal form and the methyl tert-butyl ether solvate, in WO2021250648A1. Zhong Jialiang et al. disclose nirmatrelvir solvate, crystal form A, its preparation method and its application in patent CN116462735A, specifically disclose isobutyl acetate solvate. Shi Di'er et al. disclose nirmatrelvir ethyl acetate solvate in the article (Acta Pharmaceutica Sinica 2023,58(10):3116-3122). Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a nirmatrelvir triethylenediamine cocrystal, its preparation method and its application. This cocrystal has good solubility and purity; the preparation method of this cocrystal is simple and has low cost, and is suitable for new drug development and industrial production.

[0007] The present invention provides a eutectic of a compound represented by Formula I, in which the molar ratio of nirmatrelvir to triethylenediamine is 1:1. The X-ray powder diffraction pattern of the eutectic represented by 2θ angle using Cu-Kα radiation has diffraction peaks at 6.259±0.2°, 7.081±0.2°, 8.281±0.2°, 10.500±0.2°, 11.480±0.2°, 11.944±0.2°, 12.541±0.2°, 12.701±0.2° and 12.877±0.2°.

[0008]

[0009] In some embodiments, the X-ray powder diffraction pattern of the eutectic represented by 2θ angle using Cu-Kα radiation may further have diffraction peaks at one or more of the following positions: 14.258±0.2°, 15.820±0.2°, 16.098±0.2°, 16.821±0.2°, 17.103±0.2°, 18.521±0.2°, 18.857±0.2°, 19.224±0.2° and 20.302±0.2°.

[0010] In some embodiments, the X-ray powder diffraction pattern of the eutectic represented by 2θ angle using Cu-Kα radiation may further have diffraction peaks at one or more of the following positions: 20.580±0.2°, 20.903±0.2°, 21.199±0.2°, 22.101±0.2°, 23.079±0.2°, 23.241±0.2°, 23.762±0.2°, 23.984±0.2°, 25.563±0.2° and 28.520±0.2°.

[0011] In some embodiments, the diffraction peak positions and relative peak height intensities of the X-ray powder diffraction pattern of the eutectic represented by 2θ angle using Cu-Kα radiation may also be as shown in Table 1:

[0012] Table 1

[0013]

[0014]

[0015] In some embodiments, the diffraction peak positions, interplanar spacings, peak heights and relative peak height intensities of the X-ray powder diffraction pattern of the eutectic represented by 2θ angle using Cu-Kα radiation may also be as shown in Table 2:

[0016] Table 2

[0017]

[0018]

[0019] In some embodiments, for the eutectic, the X-ray powder diffraction pattern represented by the 2θ angle using Cu-Kα radiation, the diffraction peak positions, interplanar spacings, peak heights, relative peak intensities, peak areas, relative peak areas, and full widths at half maximum may also be as shown in Table 3:

[0020] Table 3

[0021]

[0022]

[0023] In some embodiments, the X-ray powder diffraction pattern represented by the 2θ angle using Cu-Kα radiation for the eutectic may also be substantially as Figure 2 shown.

[0024] In some embodiments, the eutectic may be monoclinic, with a space group of P21 and unit cell parameters of α = 90.00°, β = 103.549(3)°, and γ = 90.00°, and its unit cell volume is

[0025] In some embodiments, for the eutectic, the first endothermic peak in the differential scanning calorimetry analysis graph may appear at 165.63°C ± 3°C, and the peak value of the endothermic peak may appear at 184.27°C ± 3°C.

[0026] In some embodiments, for the eutectic, weight loss may start at 78°C ± 3°C in the thermogravimetric analysis graph.

[0027] In some embodiments, for the eutectic, 18.24% weight loss may occur at 260°C ± 3°C in the thermogravimetric analysis graph.

[0028] In some embodiments, for the eutectic, decomposition may start at 260°C ± 3°C and be complete at 350°C ± 3°C in the thermogravimetric analysis graph.

[0029] In some embodiments, the differential scanning calorimetry analysis graph for the eutectic may also be substantially as Figure 3 shown.

[0030] In some embodiments, the thermogravimetric analysis graph for the eutectic may also be substantially as Figure 3 shown.

[0031] The present invention also provides a method for preparing the eutectic of the compound shown in Formula I. Nirmatrelvir is crystallized out in a solvent to obtain the nirmatrelvir triethylenediamine eutectic; wherein, the solvent is triethylenediamine, a mixed solvent of triethylenediamine and methyl acetate, or a mixed solvent of triethylenediamine, methyl acetate and cyclohexane.

[0032] In some embodiments, in the preparation method, the mass-volume ratio of nirmatrelvir to the solvent is 5 - 125 mg / mL, preferably 25 mg / mL, 50 mg / mL, 60 mg / mL or 80 mg / mL.

[0033] In some embodiments, in the preparation method, the molar ratio of nirmatrelvir to triethylenediamine is 1:1.

[0034] In some embodiments, in the preparation method, the mass-volume ratio of nirmatrelvir to methyl acetate is 5 - 125 mg / mL, preferably 25 mg / mL, 50 mg / mL, 60 mg / mL or 80 mg / mL.

[0035] In some embodiments, in the preparation method, the volume ratio of methyl acetate to cyclohexane is (1 - 5):(4 - 18), preferably 1:4.

[0036] In some embodiments, in the preparation method, the nirmatrelvir triethylenediamine eutectic can be prepared by conventional operations in the art, preferably by heating and dissolving, and the temperature of the heating is preferably 40 - 50 °C.

[0037] In some embodiments, in the preparation method, filtration can be performed after dissolution, and the filtration can be a conventional operation in the art, preferably normal pressure and normal temperature filtration.

[0038] In some embodiments, the crystallization method can be natural evaporation crystallization or cooling crystallization.

[0039] In some embodiments, in the preparation method, the crystallization method can be a conventional method for such operations in the art, preferably natural evaporation crystallization or cooling crystallization.

[0040] In some embodiments, in the preparation method, the natural evaporation crystallization method can be natural evaporation crystallization after heating and dissolving and then naturally cooling to room temperature; the cooling crystallization can be crystallization after heating and dissolving and then cooling to room temperature.

[0041] In some embodiments, in the preparation method, the crystallization time can be 2 - 150 h, preferably 110 - 120 h or 2 - 6 h.

[0042] In some embodiments, in the preparation method, after crystallization, the following post-treatment steps may further be included: filtration and drying.

[0043] In some embodiments, in the post-treatment steps, the filtration may be under the conventional conditions and operations of such operations in the art, preferably filtration at normal temperature and pressure; the drying may be under the conventional conditions and operations of such operations in the art, preferably drying at normal temperature and pressure.

[0044] In some embodiments, nirmatrelvir and triethylenediamine are added to methyl acetate in a molar ratio of 1:1, heated to 40 - 50 °C and stirred until dissolved, filtered, the filtrate is naturally evaporated until white crystalline solids appear, the crystals are filtered, and dried, then it is ready.

[0045] In some embodiments, nirmatrelvir and triethylenediamine are added to a mixed solution of methyl acetate and n-hexane in a molar ratio of 1:1, heated to 40 - 50 °C and stirred until dissolved, stirred at room temperature for 2 hours, the crystals are filtered, and dried, then it is ready.

[0046] The present invention also provides an application of nirmatrelvir triethylenediamine co-crystal form A in the preparation of anti-COVID-19 drugs.

[0047] The crystal form of the present invention can be identified by one or several solid-state analysis methods. Such as X-ray powder diffraction, single-crystal X-ray diffraction, differential scanning calorimetry, thermogravimetric curve, etc. Those skilled in the art know that the peak intensity and / or peak situation of X-ray powder diffraction may vary due to different experimental conditions. At the same time, due to the different precisions of the instruments, the measured 2θ values will have an error of about ±0.2°. And the relative intensity value of the peak depends more on certain properties of the measured sample, such as the crystal size and purity. Despite experimental errors, instrumental errors, and preferred orientation, etc., those skilled in the art can still obtain sufficient information to identify each crystal form from the X-ray powder diffraction data provided in this application. In DSC measurement, according to the heating rate, crystal shape, purity, and other measurement parameters, the initial temperature, maximum temperature, and heat of fusion data of the measured endothermic peak all have a certain degree of variability.

[0048] On the basis of conforming to the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0049] The reagents and raw materials used in the present invention are all commercially available.

[0050] The positive and progressive effects of the present invention are as follows:

[0051] 1. The nirmatrelvir triethylenediamine co-crystal provided in this application has good solubility, is easier to preserve, and is suitable for new drug development and industrial production.

[0052] 2. The preparation method of the nirmatrelvir triethylenediamine cocrystal of the present application has a simple process route and low cost, and is suitable for industrial production.

[0053] 3. The preparation method of the nirmatrelvir triethylenediamine cocrystal of the present application produces a cocrystal with relatively uniform particle size, which is suitable for tablet pressing production in the preparation. Brief Description of the Drawings

[0054] Figure 1 It is the unit cell diagram of the nirmatrelvir triethylenediamine cocrystal prepared in Example 1;

[0055] Figure 2 It is the measured X and simulated X-ray powder diffraction patterns of the nirmatrelvir triethylenediamine cocrystal prepared in Example 1;

[0056] Figure 3 It is the differential scanning calorimetry curve and thermogravimetric analysis curve of the nirmatrelvir triethylenediamine cocrystal prepared in Example 1;

[0057] Figure 4 It is the 1H-NMR diagram of the nirmatrelvir triethylenediamine cocrystal prepared in Example 1;

[0058] Figure 5 It is the regression equation diagram of the relationship between concentration and peak area in the equilibrium solubility test;

[0059] Figure 6 It is the intrinsic dissolution curve. Detailed Description of the Invention

[0060] The above content of the present invention will be further described in detail below through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention.

[0061] It should be understood that slightly different melting point readings may be obtained using different types of equipment or different measurement conditions. The correct melting point values of different crystal forms will be affected by the sample weight, heating rate, particle size, and calibration and maintenance of the testing equipment. The provided values cannot be used as absolute values.

[0062] It should be understood that slightly different XRPD patterns and peak values may be obtained using different types of equipment or different measurement conditions. The patterns, peak values, and relative intensities of each diffraction of different crystal forms are affected by the pretreatment method of the sample, scanning speed, particle size, and calibration and maintenance of the testing equipment. The provided values cannot be used as absolute values.

[0063] Detection Method:

[0064] 1. Single Crystal X-ray Diffraction

[0065] Instrument: SMART APEX-II (Bruker, Germany)

[0066] Wavelength:

[0067] Target: Cu-Kα radiation

[0068] Detector: Bruker APEX-II CCD

[0069] 2. Powder X-ray diffraction

[0070] Instrument: D8 Advance X-ray diffractometer (Bruker, Germany)

[0071] Wavelength:

[0072] Target: Cu-Kα radiation

[0073] Tube voltage: 40 kV

[0074] Tube current: 40 mA

[0075] Step size: 0.02°

[0076] Scanning speed: 16° / min

[0077] 3. Differential scanning calorimetry

[0078] Instrument: TA Q2000 differential scanning calorimeter (TA, USA)

[0079] Temperature range: 30 - 300 °C

[0080] Heating rate: 10 °C / min

[0081] 4. Thermogravimetric analysis

[0082] Instrument: TA Q500 thermogravimetric analyzer (TA, USA)

[0083] Temperature range: 30 - 350 °C

[0084] Heating rate: 10 °C / min

[0085] 5. Nuclear magnetic resonance spectrometer

[0086] Instrument: 600 MHz nuclear magnetic resonance spectrometer (Bruker, Germany)

[0087] Solution: DMSO-d6

[0088] 6. High performance liquid chromatograph

[0089] Instrument: U3000 high performance liquid chromatograph (Thermo Fisher)

[0090] Chromatographic column: CHIRALCEL OD-RH HPLC column (Daicel, 4.6 mm × 150 mm, 5 μm)

[0091] Detection wavelength: 220 nm

[0092] Mobile phase: water: acetonitrile = 67:33

[0093] Flow rate: 1 mL / min

[0094] 7. Dissolution tester

[0095] Instrument: Agilent Technologies 708-DS (Japan)

[0096] Sampling station: Agilent Technologies 850-DS (Japan)

[0097] 8. Particle size analyzer

[0098] Instrument: HELOS (H4605) & OASISDRY / L, R5

[0099] Analysis software: PAQXOS 5.0.5

[0100] Trigger conditions: start when Copt ≥ 0.5; valid test when 0.5% ≤ Copt ≤ 5%; end when Copt ≤ 0.5% for 1 s or actual time of 60 s

[0101] Dispersion method: Injector with a pressure of 1 bar, VIBRI vacuum of 32.00 mbar, injection rate of 30%, lift height of 0.5 mm

[0102] Example 1

[0103] Preparation of nirmatrelvir triethylenediamine cocrystal form A

[0104] The nirmatrelvir API was synthesized and characterized by crystal structure according to the method disclosed by Jiang et al. in (Reaction Chemistry & Engineering. Synthesis and crystal characteristics of nirmatrelvir. 2023, 8: 1747 - 1759), wherein the nirmatrelvir crystal form is a solvent-free crystal form.

[0105] 10 mg of nirmatrelvir (purity 98.43%) and 2.24 mg of triethylenediamine were dissolved in 0.4 mL of methyl acetate, heated and stirred at 40 - 50 °C for 20 min to dissolve, filtered, and the filtrate was naturally evaporated at room temperature. After 5 days, white blocky crystal form A appeared, with a crystal form yield of 99.5% and a measured purity of 98.58% by HPLC.

[0106] The single crystal sample obtained in Example 1 was determined by single crystal X-ray diffraction, and the obtained sample was the single crystal molecular structure diagram of crystal form A, as shown in Figure 1 shown. Crystal form A is composed of 1 molecule of nirmatrelvir and 1 molecule of triethylenediamine. It is a monoclinic crystal, its space group is P21, and its unit cell parameters are α = 90.00°, β = 103.549(3)°, and γ = 90.00°, and its unit cell volume is

[0107] The sample of Example 1 was ground and then determined by X-ray powder diffraction pattern. The X-ray powder diffraction pattern is as shown in Figure 2 shown, and the specific data of the X-ray powder diffraction represented by the 2θ angle are shown in Table 4. After confirmation, no crystal form transformation occurred before and after the sample was ground.

[0108] Table 4

[0109]

[0110]

[0111] The hydrogen spectrum of the sample of Example 1 was measured as shown in Figure 4 shown, and the specific information of the hydrogen spectrum is as follows:

[0112] 1 H NMR(600 MHz, DMSO-d6) δ 9.40(s, 1H), 9.01(s, 1H), 7.66(s, 1H), 4.97(ddd, J = 10.8, 8.5, 5.1 Hz, 1H), 4.41(s, 1H), 4.15(s, 1H), 3.91(dd, J = 10.4, 5.5 Hz, 1H), 3.79(s, 2H), 3.69(d, J = 10.4 Hz, 1H), 3.14(t, J = 9.1 Hz, 1H), 3.04(td, J = 9.3, 7.1 Hz, 1H), 2.44–2.34(m, 1H), 2.19–2.04(m, 2H), 2.01(s, 3H), 1.85(s, 1H), 1.76–1.64(m, 2H), 1.57(dd, J = 7.6, 5.5 Hz, 1H), 1.32(d, J = 7.6 Hz, 1H), 1.03(s, 3H), 0.98(s, 9H), 0.88(s, 6H), 0.85(s, 3H) [nirmatrelvir]; 2.60(s, 12H) [triethylenediamine]. The NMR data indicate that the ratio of nirmatrelvir API to triethylenediamine is 1:1.

[0113] The differential scanning calorimetry diagram of the sample of Example 1 is as shown in Figure 3As shown in Figure 3 It can be seen that this crystal form is nirmatrelvir triethylenediamine crystal form A. The first endothermic peak appears at 165.63 °C, and the peak value of the endothermic peak appears at 184.27 °C.

[0114] The thermogravimetric analysis diagram of the sample of Example 1 is as shown in Figure 3 It can be seen that the eutectic starts to lose weight at 78 °C, loses 18.24% of its weight at 260 °C, and exactly loses all the triethylenediamine in the eutectic at this point, indicating that the molar ratio of triethylenediamine to nirmatrelvir in the eutectic is 1:1; it starts to decompose at 260 °C and decomposes completely at 350 °C.

[0115] Example 2

[0116] Preparation of nirmatrelvir triethylenediamine eutectic crystal form A

[0117] The nirmatrelvir raw material drug was synthesized and characterized by crystal structure according to the method disclosed by Jiang et al. in (Reaction Chemistry & Engineering. Synthesis and crystal characteristics of nirmatrelvir. 2023, 8: 1747 - 1759). Among them, the crystal form of nirmatrelvir is a solvent-free crystal form.

[0118] 10 mg of nirmatrelvir (purity 98.43%) and 2.24 mg of triethylenediamine were dissolved in a mixed solvent of 0.2 mL of methyl acetate and 0.8 mL of cyclohexane, heated and stirred to dissolve at 40 - 50 °C, stirred at room temperature for 2 hours, filtered after a white suspension appeared, and dried at 25 °C. The yield was 99.5%, and the purity measured by HPLC was 98.70%. The obtained crystal form was detected by X-ray powder diffraction, and the X-ray powder diffraction pattern was basically consistent with Figure 2 The results are basically the same, and the characteristic peak positions are shown in Table 4.

[0119] Example 3

[0120] The inventors of the present invention studied and compared the isobutyl acetate solvate crystal form of nirmatrelvir, the isopropanol solvate crystal form of nirmatrelvir, the ethyl acetate solvate crystal form of nirmatrelvir, the methyl tert-butyl ether solvate crystal form of nirmatrelvir, the raw material crystal form of nirmatrelvir and the nirmatrelvir triethylenediamine eutectic crystal form A of the present application.

[0121] Test samples:

[0122] The crystalline form of nirmatrelvir raw material was synthesized by referring to the method disclosed by Jiang et al. in (Reaction Chemistry & Engineering. Synthesis and crystal characteristics of nirmatrelvir. 2023, 8: 1747-1759) and was confirmed to be the crystalline form of nirmatrelvir raw material in the article by XRPD;

[0123] The isobutyl acetate solvate crystalline form of nirmatrelvir was prepared by the method of patent CN116462735A and was confirmed to be the isobutyl acetate solvate crystalline form of nirmatrelvir in patent CN116462735A by XRPD;

[0124] The isopropyl alcohol solvate crystalline form of nirmatrelvir was prepared by the preparation method in patent CN114644681A and was confirmed to be the isopropyl alcohol solvate crystalline form of nirmatrelvir prepared in patent CN114644681A by XRPD;

[0125] The methyl tert-butyl ether solvate crystalline form of nirmatrelvir was prepared by the preparation method in patent WO2021250648A1 and was confirmed to be the methyl tert-butyl ether solvate crystalline form of nirmatrelvir prepared in patent WO2021250648A1 by XRPD;

[0126] The ethyl acetate solvate crystalline form of nirmatrelvir was prepared by the preparation method of Stier et al. in the article (Acta Pharmaceutica Sinica 2023, 58(10): 3116-3122). The purity of the nirmatrelvir raw material used was 98.43%; it was confirmed to be the ethyl acetate solvate crystalline form of nirmatrelvir prepared in the article by XRPD.

[0127] Investigation conditions: 1. Equilibrium solubility test

[0128] The equilibrium solubility test measures the concentration of a compound when the solution and the solid are in equilibrium in a saturated solution with an excess of solid present, which is a dynamic equilibrium process of solid dissolution and precipitation from the solution. It can be used to evaluate the solubility of a drug in vitro.

[0129] Accurately weighed 100.0 mg samples (purity 98.43%) were separately added to screw-cap test tubes containing 20 mL of pH 1.2 HCl medium (simulating gastric juice) and neutral phosphate buffered saline medium (pH 6.8). The suspension was stirred at 100 rpm and the water bath temperature was 37°C. After 3 days, 1 mL of the solution was collected from each test tube and diluted to 10 mL. Aliquots (2 mL) of the samples were filtered through a 0.45 μm membrane filter and analyzed using HPLC, and then the solubility test was carried out in triplicate.

[0130] Standard curve: Weigh accurately 10.0 mg of the sample (purity 98.43%) and add it to a 10 mL volumetric flask. Then dilute it to a stock solution of 1.00 mg / mL with acetonitrile and water in a ratio of 1:1. Dilute the stock solution with acetonitrile to standard working solutions with concentrations of 0.00625 mg / mL, 0.0125 mg / mL, 0.025 mg / mL, 0.05 mg / mL, 0.1 mg / mL, and 0.2 mg / mL. Using acetonitrile as the blank control, record the regression equation for the relationship between concentration (mg / mL) and peak area (mAu·min).

[0131] Experimental results and discussion: The linear regression equation graph is: Y = 0.1183 + 91.15224X, R 2 = 0.99995, as Figure 5 shown.

[0132] The solubility data of nirmatrelvir isobutyl acetate solvate crystal form, nirmatrelvir isopropyl alcohol solvate crystal form, nirmatrelvir methyl tert-butyl ether solvate crystal form, nirmatrelvir ethyl acetate solvate crystal form, nirmatrelvir API crystal form, and nirmatrelvir triethylenediamine cocrystal form A after three days are shown in Table 5.

[0133] Table 5

[0134]

[0135] As can be seen from Table 5, nirmatrelvir triethylenediamine cocrystal form A has good solubility at pH 1.2 and 6.8, which are 1.04 mg / mL and 0.98 mg / mL respectively. The solubility of nirmatrelvir API crystal form is low at both pH 1.2 and 6.8, which are 0.81 mg / mL and 0.78 mg / mL respectively. The solubility of the other solvate crystal forms is lower than that of the cocrystal form A obtained in this application.

[0136] Investigation conditions: 2. Intrinsic dissolution test

[0137] Intrinsic dissolution measurement is very important in the development process of chemical drugs because it can predict potential bioavailability problems.

[0138] Separate powder samples (100 mg of the crystalline form of nirmatrelvir API, 100 mg of the isobutyl acetate solvate crystalline form of nirmatrelvir, 100 mg of the isopropyl alcohol solvate crystalline form of nirmatrelvir, 100 mg of the methyl tert-butyl ether solvate crystalline form of nirmatrelvir, 100 mg of the ethyl acetate solvate crystalline form of nirmatrelvir, and 100 mg of the triethylenediamine cocrystal form A of nirmatrelvir) were pressed into a steel cylinder (cylinder diameter 6.0 mm). The dissolution medium was 1000 mL of deionized water, and 13 sampling time points were set at 3 min, 5 min, 7 min, 10 min, 15 min, 20 min, 25 min, 30 min, 45 min, 60 min, 90 min, and 120 min. The water bath temperature was maintained at 37 ± 0.2 °C. Each time 2 mL of the sample was taken, and the same volume of the dissolution medium was replenished. Insoluble particles were filtered off with a 0.45 μm membrane, and the same volume of the dissolution medium was replenished. 1 mL of the mother liquor was taken and added to 0.5 mL of acetonitrile solution to prepare the injection solution. After the solution was filtered, it was detected by a high performance liquid chromatograph, and the concentration of the drug at each time point was calculated according to the standard curve. A total of 3 parallel experiments were carried out.

[0139] The intrinsic dissolution value was calculated according to formula (1).

[0140] G = (dw / dt) / S (1)

[0141] In the formula: G is the intrinsic dissolution value (μg / min / cm 2 ); dw is the change in drug dissolution (μg); dt represents the change in time (min); S represents the compressed surface area (cm 2 ).

[0142] The results are shown in Table 6 and Figure 6 as follows.

[0143] Table 6

[0144]

[0145] The lowest intrinsic dissolution value of the crystalline form of nirmatrelvir API was 0.002 mg / min / cm 2 , the intrinsic dissolution value of the isobutyl acetate solvate crystalline form of nirmatrelvir was 0.0865 mg / min / cm 2 , the intrinsic dissolution value of the isopropyl alcohol solvate crystalline form of nirmatrelvir was 0.0897 mg / min / cm 2 , the intrinsic dissolution value of the methyl tert-butyl ether solvate crystalline form of nirmatrelvir was 0.1161 mg / min / cm 2 , the intrinsic dissolution value of the ethyl acetate solvate crystalline form of nirmatrelvir was 0.0615 mg / min / cm 2。The highest dissolution rate of nirmatrelvir triethylenediamine cocrystal form A is 0.2878 mg / min / cm 2 。The order of their intrinsic dissolution values is nirmatrelvir triethylenediamine cocrystal form A > nirmatrelvir methyl tert-butyl ether solvate crystal form > nirmatrelvir isopropanol solvate crystal form > nirmatrelvir isobutyl acetate solvate crystal form > nirmatrelvir raw material crystal form. Generally, nirmatrelvir triethylenediamine cocrystal form A is considered to have a higher bioavailability.

[0146] Investigation conditions: 3. Particle size distribution test

[0147] The particle morphology and particle size affect the rearrangement and interaction mode of powder particles in the tablet pressing die, and thus determine the final properties of the powder. The particle morphology will affect the mode of particle rearrangement in the plane and determine the type of bonding between particles, such as interlocking or bonding in the form of a solid bridge. During the compression process of drug powder particles, the particle shape and surface roughness will affect the tablet pressing performance of the powder. The friction and adhesion between irregularly shaped particles with a rough surface in the plane are enhanced, making the tablet pressing performance of the powder enhanced.

[0148] The obtained nirmatrelvir triethylenediamine cocrystal form A, nirmatrelvir methyl tert-butyl ether solvate crystal form, nirmatrelvir isopropanol solvate crystal form, nirmatrelvir isobutyl acetate solvate crystal form, and nirmatrelvir raw material crystal form were sieved through a 300-mesh sieve and then tested on a HELOS (H4605)&OASISDRY / L laser particle size analyzer. Each sample was tested in parallel three times. Using a pressure of 1 bar, a vacuum of 32 mbar, an injection rate of 30%, and starting the test at Copt≥0.5%, the effective test data of 0.5%≤Copt≤5% were taken, and D 10 、D 50 、D 90 was used to evaluate the particle size distribution.

[0149] Table 7

[0150]

[0151]

[0152] Note: “**” represents the RSD of the results of three parallel tests for each sample.

[0153] As can be seen from Table 7, the D 50 of nirmatrelvir triethylenediamine cocrystal form A is 26.60±2.62 μm, having a relatively average powder particle size. The D 90 is 159.81±56.06 μm, which is smaller than all existing solvates at present. During the compression process of drug powder particles, it makes the tablet pressing performance of the powder enhanced and is more conducive to the tablet pressing process of the preparation.

Claims

1. A eutectic of a compound represented by Formula I, characterized in that, In the eutectic described above, the molar ratio of nirmatrelvir to triethylenediamine is 1:

1. The X-ray powder diffraction pattern of the eutectic using Cu-Kα radiation and expressed in terms of 2θ has diffraction peaks at 6.259 ± 0.2°, 7.081 ± 0.2°, 8.281 ± 0.2°, 10.500 ± 0.2°, 11.480 ± 0.2°, 11.944 ± 0.2°, 12.541 ± 0.2°, 12.701 ± 0.2° and 12.877 ± 0.2°.

2. The eutectic according to claim 1, characterized in that, The X-ray powder diffraction pattern of the eutectic using Cu-Kα radiation and expressed in terms of 2θ also has diffraction peaks at one or more of the following positions: 14.258 ± 0.2°, 15.820 ± 0.2°, 16.098 ± 0.2°, 16.821 ± 0.2°, 17.103 ± 0.2°, 18.521 ± 0.2°, 18.857 ± 0.2°, 19.224 ± 0.2° and 20.302 ± 0.2°.

3. The eutectic according to claim 2, characterized in that, The X-ray powder diffraction pattern of the eutectic using Cu-Kα radiation and expressed in terms of 2θ also has diffraction peaks at one or more of the following positions: 20.580 ± 0.2°, 20.903 ± 0.2°, 21.199 ± 0.2°, 22.101 ± 0.2°, 23.079 ± 0.2°, 23.241 ± 0.2°, 23.762 ± 0.2°, 23.984 ± 0.2°, 25.563 ± 0.2° and 28.520 ± 0.2°.

4. The eutectic according to claim 3, wherein The X-ray powder diffraction pattern of the eutectic using Cu-Kα radiation and expressed in terms of 2θ, the diffraction peak positions and the relative intensities of the peak heights are shown in the following table: 。 5. The eutectic according to claim 4, wherein, The X-ray powder diffraction pattern of the eutectic using Cu-Kα radiation and expressed in terms of 2θ, the diffraction peak positions, interplanar spacings, peak heights, relative intensities of peak heights, peak areas, relative intensities of peak areas and full widths at half maximum are shown in the following table: 。 6. The eutectic according to claim 1, characterized in that, The eutectic satisfies one or more of the following conditions: 1) The X-ray powder diffraction pattern of the eutectic using Cu-Kα radiation and expressed in terms of 2θ is substantially as shown in Figure 2; 2) For the eutectic, the first endothermic peak in the differential scanning calorimetry analysis diagram appears at 165.63 °C ± 3 °C, and the peak value of the endothermic peak appears at 184.27 °C ± 3 °C; 3) For the eutectic, weight loss starts at 78 °C ± 3 °C in the thermogravimetric analysis diagram; and 4) For the eutectic, 18.24% weight loss occurs at 260 °C ± 3 °C in the thermogravimetric analysis diagram.

7. The eutectic according to claim 1, characterized in that, The eutectic satisfies one or more of the following conditions: 1) The eutectic is monoclinic, with a space group of P21 and lattice parameters of α = 90.00°, β = 103.549(3)°, and γ = 90.00°, and the unit cell volume is 2) For the eutectic, the differential scanning calorimetry analysis diagram is substantially as shown in Figure 3; and 3) For the eutectic, the thermogravimetric analysis diagram is substantially as shown in Figure 3.

8. A method for preparing a eutectic as described in any one of claims 1-7, characterized in that, Nirmatrelvir is crystallized in a solvent to obtain nirmatrelvir triethylenediamine eutectic; wherein, the solvent is triethylenediamine, a mixed solvent of triethylenediamine and methyl acetate, or a mixed solvent of triethylenediamine, methyl acetate and cyclohexane.

9. The method for preparing the eutectic according to claim 8, characterized in that, The preparation method of the eutectic satisfies one or more of the following conditions: 1) The molar ratio of nirmatrelvir to triethylenediamine is 1:1; 2) The mass-volume ratio of nirmatrelvir to methyl acetate is 5 - 125 mg / mL, preferably 25 mg / mL, 50 mg / mL, 60 mg / mL or 80 mg / mL; 3) The volume ratio of methyl acetate to cyclohexane is (1 - 5):(4 - 18), preferably 1:4; 4) The cocrystal is prepared by heating and dissolving, and the heating temperature is preferably 40 - 50 °C; 5) The crystallization method is natural evaporation crystallization or cooling crystallization; The natural evaporation crystallization method can be natural evaporation crystallization after natural cooling to room temperature after heating and dissolving; The cooling crystallization can be crystallization after cooling to room temperature after heating and dissolving; and 6) After crystallization, the following post-treatment steps are further included: filtration and drying; The filtration can be filtration under normal temperature and pressure; The drying can be drying under normal temperature and pressure.

10. Use of a cocrystal according to any one of claims 1 - 7 in the preparation of an anti-COVID-19 drug.

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